Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000527.5(LDLR):c.2389+5G>A

CA10585843

252306 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: df6304d1-7467-43e4-9247-ec974c37229f

HGVS expressions

NM_000527.5:c.2389+5G>A
NM_000527.5(LDLR):c.2389+5G>A
NC_000019.10:g.11128090G>A
CM000681.2:g.11128090G>A
NC_000019.9:g.11238766G>A
CM000681.1:g.11238766G>A
NC_000019.8:g.11099766G>A
NG_009060.1:g.43710G>A
ENST00000558518.6:c.2389+5G>A
ENST00000252444.9:n.2643+5G>A
ENST00000455727.6:c.1885+5G>A
ENST00000535915.5:c.2266+5G>A
ENST00000545707.5:c.1855+5G>A
ENST00000557933.5:c.2389+5G>A
ENST00000558013.5:c.2389+5G>A
ENST00000558518.5:c.2389+5G>A
ENST00000560628.1:n.108+436G>A
NM_000527.4:c.2389+5G>A
NM_001195798.1:c.2389+5G>A
NM_001195799.1:c.2266+5G>A
NM_001195800.1:c.1885+5G>A
NM_001195803.1:c.1855+5G>A
NM_001195798.2:c.2389+5G>A
NM_001195799.2:c.2266+5G>A
NM_001195800.2:c.1885+5G>A
NM_001195803.2:c.1855+5G>A

Uncertain Significance

Met criteria codes 4
PP4 PP3 PS4_Supporting PM2
Not Met criteria codes 17
BS2 BS4 BS3 BS1 BP2 BP3 BP4 PS2 PS3 PS1 BA1 PP1 PM6 PM3 PM1 PM4 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.2389+5G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). So PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 4.93; canonical donor wt = 9.86. Ratio: 4.93/9.86 = 0.5 ---- It is below 0.8 Variant is predicted to alter splicing. So PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met.
Met criteria codes
PP4
Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met.
PP3
No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 4.93; canonical donor wt = 9.86. Ratio: 4.93/9.86 = 0.5 ---- It is below 0.8 Variant is predicted to alter splicing. So PP3 is met.
PS4_Supporting
Variant meets PM2 and is identified in 2 unrelated index cases with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). So PS4_Supporting is met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. So PM2 is met.
Not Met criteria codes
BS2
No data available.
BS4
No data available.
BS3
No data available.
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BP2
No data available.
BP3
No in-frame deletions/insertions
BP4
No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 4.93; canonical donor wt = 9.86. Ratio: 4.93/9.86 = 0.5 ---- It is below 0.8 Variant is predicted to alter splicing.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No data available.
PS1
The current variant is in a non-coding region
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
PP1
Only 1 affected member and 1 informative meiosis.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No data available.
PM1
Not located in exon 4 and not a cysteine residue.
PM4
No in-frame deletions/insertions
PM5
The current variant is in a non-coding region
Approved on: 2023-03-20
Published on: 2023-03-31
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